The neocortex is a structure of fundamentally uniform lamination that has regional variations in cellular composition and connectivity. The major regional variation in the cellular composition of the normal neocortex is the presence and relative development of a granular Layer IV, principal target of thalamic afference, composed of various types of stellate cells and other nonpyramidal cells. In experimental manipulations of development, a normally granular cortex can be made agranular by early thalamic lesions. Interestingly, the principal cytoarchitectonic abnormality of the cortex in Down syndrome is also the absence of Layer IV and granule cells, specifically aspinous stellate cells. Thus, the size and composition of Layer IV shows both substantial variability in the normal cortex and variability in pathology, and can be manipulated experimentally. We propose to investigate the developmental mechanisms which produce these normal and abnormal variations in the cortex using a variety of neuroanatomical techniques. By labelling neocortical cells generated on a particular embryonic days with tritiated thymidine, and following their number and distribution to maturity in cortices which normally vary in the relative size of Layer IV, and in cortices after early thalamic lesions, we will investigate the normal contribution of cell generation and cell death to this feature of cortical variability. The use of tritiated thymidine labelling of presumptive Layer IV cells in combination with other cell identification techniques, including Golgi staining, retrogradely transported HRP, fluorescent tracers and immunohistochemistry will allow us to determine which features of cell identity may vary normally and experimentally. Eventually, we will determine which features of neocortical cell identity are fixed on generation, and which features are specified or selected by cellular interactions in early development. These results will have direct implications for the understanding of pathological development of the neocortex, particularly cerebral palsy consequent to perinatal trauma and Down syndrome.